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Gene therapy unveils family tree of blood stem cells

A few weeks after bone marrow transplantation are enough for our body to regenerate its whole blood tissue, including a well-functioning immune system. Understanding how this process works would improve efficacy and safety of hematopoietic stem cell transplantations and consequently the treatment of many common diseases, e.g. tumors and autoimmune diseases. Researchers of San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) guided by Alessandro Aiuti – together with Luca Biasco (now at Harvard Medical School of Boston) – examined follow-up samples of the first children with Wiskott-Aldrich syndrome (WAS) who were treated with gene therapy, managing to trace the history of more than 140,000 transplanted cells in the five years following the treatment. The study – supported by the Italian charity Fondazione Telethon – was published today in Nature Medicine and shows the role of different stem cells families both in the earliest phase after transplantation (i.e. reconstruction of the hematopoietic system from scratch) and in the following maintenance period. The results open up new prospects in hematology and show once again that research on rare diseases produces precious knowledge and innovation.

Family trees showing different roles for different hematopoietic stem cells at early and late phases of hematopoietic reconstitution (stem cells in red, bone marrow progenitors in pink; differentiated cells in purple).

Despite its clinical and scientific importance, the process through which blood cells are continuously generated by bone marrow stem cells has always been difficult – if not impossible – to study in humans. The start of the early gene therapy clinical trials for primary immunodeficiency changed everything. This therapeutic approach – which sees SR-Tiget as a reference center in the world – requires that the patient’s bone marrow stem cells (which carry a mutated gene that causes the WAS disease) be extracted and corrected with the functioning version of the same gene. The corrected gene is transported into the cells’ nucleuses by a virus previously deprived of its replicative content. Once corrected, cells are reintroduced into the patient’s bone marrow where they can duplicate and differentiate into all the other blood cells.

“The insertion of the corrected gene into the cells’ DNA not only allows to produce healthy and functional cells, but it also permits to examine what happens to each of them along the months and the years following transplantation” says Alessandro Aiuti, deputy director of SR-Tiget and full professor at Università Vita-Salute San Raffaele. “That is because the corrected gene positions itself in random DNA spots of every cell. So its coordinates become some sort of bar code or tag that make every stem cell – as well as every blood cell it produces – identifiable”.

Researchers examined blood and bone marrow samples taken from patients affected by WAS during their first five years of follow-up, they ‘counted up’ the cells and classified them according to their specific type. Then, thanks to mathematical models, they managed to build an actual family tree and discovered there are specific stem cells families with different roles in the blood regeneration process. Some types are crucial in the months that follow the transplant, when the blood tissue needs to be reconstructed quickly from scratch. Others remain inactive until they come into action to give their contribute in the so-called stationary phase, when the tissue needs to be kept healthy. “One of the most surprising discoveries – that might actually have direct consequences for bone marrow transplantation – is that stem cells producing lymphocytes are able to keep their population stable autonomously, with no need to be constantly recreated by less specialized stem cells” continues Serena Scala, young researcher at SR-Tiget and one of the first authors of the paper.

“This study shows once again that quality scientific research on rare diseases not only can give a normal life to children and families who lost hope but it can also generate knowledge and applications for the good of everybody” concludes Alessandro Aiuti.